Quelle:
https://www.edisoninvestmentresearch.com/research/...uticals/preview/Therapeutische Anwendung:
Three Phase II checkpoint inhibitor combo studies planned. Targeting US/Australia IND filings Q418
TLX250 ccRCC therapeutic
Telix is also developing TLX250, a MTR therapeutic targeting ccRCC. TLX250 is based on a modified and improved version of the mAb girentuximab (cG250) labelled with the isotope 177Lu. 177Lu is an ideal isotope for therapeutic MTR applications because it emits beta particles that travel only a short distance in tissue and are absorbed within the tumour, killing cancer cells. It has a comparatively short half-life of 6.64 days.
Wilex has completed two clinical studies of 177Lu-cG250 in patients with metastatic ccRCC. The two studies provided encouraging evidence of efficacy, with 78% and 68% of patients achieving responses of stable disease or better in the three months after the first course of treatment in the Phase I and Phase II studies, respectively. One of the 14 patients in the Phase II study achieved a partial response. While the treatment was generally well tolerated, a high proportion of subjects experienced myelosuppression (low levels of white blood cell production in the bone marrow). We expect the company to seek to optimise the dosing regimen (both amount and interval) in future studies to in order to reduce the incidence of this side effect. The company’s experience with MTR therapies in prostate cancer will help inform the programme to optimise the dosing regimen.
Better treatments are needed for metastatic ccRCC
While many patients who are diagnosed with early-stage RCC can be cured by surgical treatment, better treatments are needed for metastatic disease, where the five-year survival rate is only 12%.
Checkpoint inhibitors and targeted therapies (antiangiogenic therapies and mTOR inhibitors) are the mainstays of systemic treatment for unresectable and metastatic ccRCC, rather than cytotoxic chemotherapy. According to clinical guidelines, the preferred first-line therapies are the targeted therapies pazopanib and sunitinib; ipilimumab + nivolumab combination (FDA approved April 2018) is a preferred first-line therapy for intermediate and low risk patients, but not for high-risk patients9.
Preferred second-line therapies are cabozantinib (TKI including VEGFR) and the anti-PD1 immune checkpoint inhibitor (ICI) nivolumab, which was approved by the FDA for patients with advanced RCC in November 2015.
Potential for TLX250/ICI combo to improve response rates
Therapies such as ICI that enhance immune responses have had remarkable success in treating a range of cancers, however, typically less than a third of patients respond when these drugs are used as single agents (monotherapy). For example, the response to second-line treatment of mRCC with nivolumab was 22%10.
Combining ICI with chemotherapy has been an effective way to improve response rates compared to ICI monotherapy in a number of cancer types. For example, in newly diagnosed metastatic lung cancer the response rate to the Keytruda/chemo combo in the KEYNOTE-189 study was 49.4%11, which is substantially higher than the 27.3% ORR to Keytruda monotherapy reported in the separate KEYNOTE-042 study. The synergistic benefit of ICI/chemo combos is believed to be due to the cellular debris from tumour cells killed by the chemotherapy triggering an immune response (sometimes referred to as immunogenic cancer cell death or turning immunologically cold tumours hot), with the ICI then able to strengthen this immune response.
With chemotherapy not recommended in ccRCC, there is potential for MTR to play a similar role in killing tumour cells and releasing tumour antigens to stimulate an immune response. Combining MTR with ICI would be expected to improve ORR.
The ability of radiation therapy to have immune stimulatory effects is evidenced by the well-established phenomenon of so-called abscopal responses to radiation, where tumours away from the site of radiation also respond to treatment due to an immune response triggered by the therapy12.
Phase II trials for TLX250 planned for 2019
Telix is formulating plans for three Phase II studies of TLX250 in combination with ICIs, one of which is likely to be a pharma-sponsored study. The three studies are expected to involve ~60 subjects in total. It plans to submit two INDs in relation to these studies in US/Australia in Q418. The manufacture of clinical grade material for these studies is expected to be completed by the end of August.
By the end of 2019 the company expects these studies to have produced sufficient information to identify an appropriate strategy for the Phase III development of TLX250. A key goal of the planned Phase II studies is to demonstrate that there are synergistic benefits from combining TLX250 with ICI therapy.
Umsatzschätzungen therapeutische Anwendung. HP Umsatzbeteiligung 5%.
Global peak sales of US$470m. For the US assumes 65,300 kidney cancer cases/yr, 20% eligible for treatment, 20% penetration; for the EU assumes 93,000 cases/yr, 20% eligible, 16% penetration; pricing US$70k per patient, 30% discount in Europe; launch 2024 - biologicals market exclusivity to 2036 in US, 2034 in Europe; assume receives 12% net royalty.
R&D cost: A$4m for two small company funded Phase II studies, then out-license.